ATF3/SOX11-regulated FST activates IGF1R-ERK/AKT-Sp1 signaling to sustain trigeminal neuropathic pain

Trigeminal neuropathic pain (TNP) is a severe facial pain disorder whose pathogenesis is incompletely understood. We previously identified follistatin (FST) as a contributor to peripheral nerve injury-induced neuropathic pain through direct binding to the insulin-like growth factor-1 receptor (IGF1R) in the dorsal root ganglia. However, the regulatory mechanisms governing FST expression and its specific role in TNP remain unclear. Here, we report that FST is upregulated in trigeminal ganglion (TG) neurons following partial infraorbital nerve transection (pIONT), and that this process is regulated by the transcription factors ATF3 and SOX11. Genetic deletion or knockdown of Fst attenuated pIONT-induced TNP and reduced TG neuronal hyperexcitability. Intra-TG injection of FST promoted pain-like behaviors and activated ERK and AKT signaling in an IGF1R-dependent manner. In addition, FST decreased voltage-gated potassium (K_v) channel currents and enhanced neuronal excitability via IGF1R-ERK/AKT signaling. Notably, FST upregulated a cohort of genes, including Fst itself, Cyp26a1, and Ccl2, through the transcription factor Specificity Protein 1 (Sp1). Consistently, pIONT increased Sp1 phosphorylation, and pharmacological inhibition or knockdown of Sp1 alleviated mechanical allodynia, reduced the expression of Fst, Cyp26a1, and Ccl2, and decreased the excitability of TG neurons. Collectively, these results reveal a previously unknown mechanism by which FST activates IGF1R-ERK/AKT signaling to decrease K_v channel currents and promote Sp1-regulated gene expression, contributing to peripheral sensitization and TNP pathogenesis. Our data indicate that targeting the FST-IGF1R-ERK/AKT-Sp1 axis may represent a promising therapeutic strategy for TNP.